The compounds of the present invention are analogues of the natural prostaglandin PGD.sub.1, and PGD.sub.2, PGE.sub.2, PGE.sub.1 and PGF.sub.2 alpha useful in the treatment of osteoporosis. Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid. The carbon atoms of the basic prostaglandin are numbered sequentially from the carboxylic carbon atom through the cyclopentyl ring to the terminal carbon atom on the adjacent side chain. Normally, the adjacent side chains are in the trans orientation. PGE.sub.2 has the following stricture. ##STR1## The presence of an oxo group at C-9 of the cyclopentyl moiety is indicative of a prostaglandin within the E class while PGE.sub.2 contains a trans unsaturated double bond at the C.sub.13 -C.sub.14 and a cis double bond at the C.sub.5 -C.sub.6 position. U.S. Pat. No. 4,171,331 teaches 1 and 2 substituted analogues of certain prostaglandins. Disclosed are trans 1 and 2 di(loweralkyl)phosphono; 1 and 2 chloro, bromo, and iodo; 1 and 2-thio; and 1 and 2 amino analogues of PGE.sub.1.
U.S. Pat. No. 3,927,197 discloses the formation of various acid derivatives of prostaglandins such as amides, carboxylate-amine salts, and the 2-decarboxy-2-(2,3,4,5-tetryol-1-yl) derivative.
Osteoporosis is the most common form of metabolic bone disease and is commonly observed in postmemopausal women but also occurs in elderly males and females or in young individuals. Commonly, the disease is characterized by fractures of the wrist and spine, while femoral fractures are the dominant feature of senile osteoporosis. The physical causitive factor which creates susceptibility to fracturing is the gradual loss of bone. Apparently, the normal balance of bone resorption activity by the osteoclasts (bone dissolving or resorbing cells) and bone formation activity by the osteoblasts (bone forming cells) is disrupted by development of the disease so that the cavities created by the osteoclasts are not refilled by the osteoblasts. A number of pharmaceutical compounds are known in the art which hinder the activity of osteoclasts so that bone loss is diminished. For example, bisphosphonates as a class are useful in inhibiting bone loss and are therefore important in treating diseases associated with bone loss, including osteoporosis. A more difficult treatment regime or area has been the effective acceleration or stimulation of bone formation to maintain bone growth or strengthen weakened bones.
It is clear, however, that the activity of osteoblasts and osteoclasts is coordinated and regulated by a complex mechanism and is affected by a variety of hormones and prostaglandins. See Raisz et al., Ann. Rev. Physiol., 43:225 (1981); U.S. Pat. No. 4,921,697 which teaches that inhibition of prostaglandin production by IFN-gamma is an effective treatment for osteoporosis and other bone-resorption diseases since prostaglandins have been implicated in bone loss or resorption. The literature also suggests that prostaglandins may also play an important role in bone formation. See W. Harvey and A. Bennett, "Prostaglandins in Bone Resorption" CRC Press, pp. 37 (1988). Osteoblasts are responsible for carrying out the bone formation process. It has been established that bone formation in vivo in animals is stimulated by systemic injection of PGE.sub.2. See Rodan G. J. Cell Biochem. Suppl. 0 (15 Part F), 160 (1991).
The effects of prostaglandins administered alone has been disclosed in the art. Ueno et al., Bone, 6, 79-86, (1985) administered PGE.sub.2 to rapidly growing rats at dosages of 1, 3 and 6 mg of PGE.sub.2 /Kg/day. The results showed an increase in hard tissue mass in the secondary spongiosa of the proximal tibial metaphysis and an increase in the number of trabeculae. Jee et al., Bone and Mineral, 15, 33-55 (1991), disclosed that subcutaneous injections of PGE.sub.2 over 60, 120, and 180 days produced an increased tibial diaphyseal bone mass and elevated bone activity. The authors reported that the anabolic effects of PGE.sub.2 increases periosteal and corticoendosteal bone mass and sustains the transient increase in bone mass with daily administration of PGE.sub.2. It is known that very little control is possible over the duration and the concentration at which PGs reach the bone cells. It is also known that systemic injection or infusion of PGs is an alternative with significant drawbacks since the lungs efficiently remove PGs from circulation. See W. Harvey and A. Bennett, "Prostaglandins in Bone Resorption" CRC Press, pp. 37 (1988).
It is also known that toxicity of prostaglandins due to systemic distribution of the administered drug reduces or diminishes the pharmaceutical utility of these compounds. Delivery of high doses of prostaglandins which would be necessary because of the short half life of these compounds may cause unwanted side effects. Ueno et al reported that when PGE.sub.2 was administered systemically through subcutaneous injections to rats, diarrhea and flushing of the extremities along with weight loss occurred at doses of 3 mg/Kg/day or higher. In addition, significant decreases in serum phosphate levels of 1 mg of PGE.sub.2 were noted. Jee et al reported that long term administration of PGE.sub.2 administered via subcutaneous injection resulted in soft tissue weight increases in adrenal glands, liver, kidneys, and lungs. U.S. Pat. No. 4,621,100 discloses side effects after oral dosing with PGE.sub.2 including loose stools, diarrhea, vomiting, infected sclerae, and increased serum alkaline phosphatase levels.
Frost et al. in "Treatment of Osteoporosis by Manipulation of Coherent Bone Cell Populations", Clinical Orthopedics and Related Research, 143, 227 (1979) discloses a theoretical model that suggests it should be possible to synchronize the activity and metabolism of bone cells by administering bone cell activating agents first and then administering a bone resorption inhibiting agent. This proposed model assumes that bone formation inhibition does not take place, because no bone resorption inhibiting agent is administered during the bone formation phase of the bone remodeling unit. EPO App. No. 0 381 296 teaches the use of a kit wherein a bone activating period or treatment regime is followed by a bone resorption inhibiting regime. Examples of bone activating compounds cited in this reference include parathyroid hormone (PTH), inorganic phosphate, growth hormone, fluoride, thyroid hormone (e.g. thyroxin), certain vitamin D metabolites and prostaglandins (PGE.sub.2 in a dose regime of 10 mg/kg per day). See also U.S. Pat. No. 5,118,667. Examples of bone resorption inhibiting polyphosphonates include ethane-1-hydroxy 1,1-diphosphonic acid, methane diphosphonic acid, pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro diphosphonic acid, methane hydroxy diphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, propane-3-3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid, phenyl amino methane diphosphonic acid, N,N-dimethylamino methane diphosphonic acid, N(2-hydroxyethyl) amino methane diphosphonic acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid (administered after PGE.sub.2 at a dosage per day of 0.005 mg P/kg), pentane-5-amino-1-hydroxy-1,1-diphosphonic acid, and hexane-6-amino-1-hydroxy-1,1-diphosphonic acid. Combinations of a methylene bisphosphonate coupled to a medicinal compound such as a Non-Steroidal Anti-Inflammatory Agent (NSAID) have been disclosed. See Japanese Patent Publication No. H2-104593.
U.S. Pat. No. 5,409,911, which issued on Apr. 25, 1995, describes prostaglandin-bisphosphonate compounds useful in treating bone disorders and is hereby incorporated by reference in its entirety. The compounds disclosed in U.S. Pat. No. 5,409,911 provide simultaneous delivery of a bone activating agent such as a prostaglandin that is chemically coupled to a bone resorption inhibiting compound which selectively delivers the bone activating agent to the target area. Upon gradual hydrolysis of the compound, the hydrolyzed products are able to provide bone resorption inhibiting activity (via the bisphosphonates) and bone growth or stimulating activity (via PGE.sub.2).
The compounds of the present invention are also designed to deliver both a prostaglandin and a bisphosphonate to the target bone areas. However, the compounds of the present invention unexpectedly possess a critical balance of chemical stability and lability. These compounds possess the requisite stability to allow for their formulation into a finished pharmaceutical preparation, storage and shelf stability of the pharmaceutical preparation, and administration, and also the desired lability to permit the administered active ingredient to hydrolyze in vivo to release the prostaglandin and bisphosphonate components. The compounds of the present invention bind effectively to bone both in vitro and in vivo and liberate PGE.sub.2 at an acceptable rate. The present invention also enables more effective delivery of PGE.sub.2 to the target region and therefore overcomes the serious side effect disadvantages associated with administration of larger quantities of PGE.sub.2 alone. In addition, PGE.sub.2 administered systemically has a short half-life. The present invention overcomes the disadvantages prevalent in the background art and at the same time provides a compound that promotes bone growth and deters bone resorption to provide a treatment for osteoporosis and related disorders of calcium metabolism.
It is therefore an object of the present invention to provide novel prostaglandin-bisphosphonate conjugates.
It is another object of the present invention to provide such compounds having the ability to deliver a prostaglandin locally to bone and to gradually hydrolyze so that a bone resorption inhibitor and a bone formation enhancer can be delivered directly to bone.
It is another object of the present invention to provide methods for treating and or reducing the risk of contracting disease states or conditions associated with abnormal bone resorption.
It is another object of the present invention to provide methods for treating and or reducing the risk of contracting osteoporosis.
These and other objects will become readily apparent from the detailed description which follows.